Vibrio vulnificus Infection in a Hemodialysis Patient Receiving Intravenous Iron Therapy
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MAJOR ARTICLE
Vibrio vulnificus Infection in a Hemodialysis
Patient Receiving Intravenous Iron Therapy
James C. Barton,1,2,3 Michael E. Coghlan,2 Michael T. Reymann,2 Thomas W. Ozbirn,2 and Ronald T. Acton3,4
1
Southern Iron Disorders Center, 2Department of Medicine, Brookwood Medical Center, and 3Department of Medicine and 4Immunogenetics
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Program, Departments of Microbiology and Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama
A 73-year-old man treated with long-term hemodialysis, erythropoietin, and intravenous iron sucrose infusions
developed Vibrio vulnificus infection after eating raw oysters harvested from the Alabama coast. Five of the
31 persons with cases of V. vulnificus infection reported to the Alabama Department of Public Health (Mont-
gomery) during 1996–2002 (including the patient described here) also had renal disease. Persons with renal
disease, especially those treated with long-term hemodialysis and intravenous iron infusions, may have an
increased risk of infection with V. vulnificus.
Vibrio vulnificus infections often occur in persons with iron sucrose (Venofer; American Regent Laboratories
chronic liver disease, alcoholism, diabetes mellitus, [10]) to maintain a serum transferrin saturation of
immunodeficiencies, hemochromatosis or other iron ⭓30% and a serum ferritin concentration of ⭓300 ng/
overload disorders, or HFE mutations and in persons mL [11, 12]. On the third and second days before hos-
receiving iron chelation therapy [1–5]. Persons with pital admission, the patient ate raw oysters (but no
chronic renal disease may also have increased suscep- other raw seafood) harvested in Alabama during April
tibility to Vibrio infection [6, 7], but there are few de- while he was on a visit to the Alabama coast, ∼400 km
scriptions of such cases [4, 8, 9]. Here, we describe the south of his home. Six hours after consuming the sec-
occurrence of V. vulnificus infection in a man treated ond oyster meal, he awoke with shaking chills, a tem-
with long-term hemodialysis who also received periodic perature of 40C, and severe pain and swelling of his
intravenous infusions of iron sucrose and erythropoi- left arm distal to his arteriovenous graft.
etin for management of anemia. The pertinence of ob- At a local emergency department, blood specimens
servations in the present case to the pathogenesis of,
were obtained for culture. The patient was empirically
susceptibility to, and prevention of V. vulnificus infec-
treated with single doses of vancomycin and gentamicin
tions is discussed.
and transferred to our institution for further evaluation
and treatment. There was no history of trauma to the
CASE REPORT arm or exposure to seawater. His most recent infusion
of intravenous iron sucrose had occurred 11 days before
A 73-year-old white man was treated with long-term
the onset of the present illness. He had not consumed
hemodialysis, erythropoietin, and periodic infusions of
ethanol for 20 years, but he noted a history of previous
heavy ethanol ingestion. He was admitted to hospital
with septicemia, and blood specimens were obtained
Received 18 March 2003; accepted 26 May 2003; electronically published 12
August 2003.
for additional cultures.
Financial support: Southern Iron Disorders Center (Birmingham, AL) and Expanding hemorrhagic necrotic bullae and pro-
Immunogenetics Program, Departments of Microbiology and Epidemiology and gressive tense edema were present in the left arm. The
International Health, University of Alabama at Birmingham.
findings of a physical examination did not suggest the
Reprints or correspondence: Dr. James C. Barton, Southern Iron Disorders Center,
Ste. G-105 ACC, 2022 Brookwood Medical Center Dr., Birmingham, AL 35209 occurrence of chronic liver disease. Doppler studies of
(ironmd@dnamail.com). the left upper extremity revealed no evidence of im-
Clinical Infectious Diseases 2003; 37:e63–7
2003 by the Infectious Diseases Society of America. All rights reserved.
paired arterial or venous flow. The leukocyte count was
1058-4838/2003/3705-00E2$15.00 8200 leukocytes/mm3 (including 41% segmented and
V. vulnificus, Hemodialysis, and Iron • CID 2003:37 (1 September) • e6340% band forms), the hemoglobin level was 13.6 g/dL, the Twenty-six patients were white, 3 were Asian, and 2 were Af-
mean corpuscular volume was 104.3 fL, and the platelet count rican American. Thirteen patients died of V. vulnificus infection,
was 168,000 platelets/mm3. Serum concentrations of creatinine 13 survived the infection, and the survival status was unknown
and blood urea nitrogen were 10.6 mg/dL and 87 mg/dL, re- or unreported for 5 patients.
spectively. Cultures of aspirates of the bullae revealed V. vul- Renal disease of an otherwise unspecified type was reported
nificus; the results of blood cultures from both hospitals were to be present in 4 of the 31 patients, including the patient
negative. Fasting serum concentrations of aspartate and alanine described here. It was reported that a 63-year-old white man
aminotransferases, alkaline phosphatase, and glucose were with renal disease died as a consequence of V. vulnificus infec-
within respective reference ranges. Prothrombin time was 18.2 tion of a leg wound. A 41-year-old white man with renal disease
s (international normalized ratio, 1.69); the partial thrombo- was infected via a facial wound and survived. A 46-year-old
plastin time was 36.3 s. The total serum IgG level was 1027 white man with renal disease survived V. vulnificus bacteremia
mg/dL (reference range, 700–1200 mg/dL), with normal IgG associated with eating raw oysters. The present patient is pre-
subclass concentrations. sumed to have had bacteremia, because this is the most com-
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On the 18th hospital day, serum iron measurements revealed mon manifestation of V. vulnificus infection associated with
the following values: iron, 51 mg/dL; transferrin saturation, eating raw oysters and the usual primary site of infection in
35%; and ferritin, 776 ng/mL. HFE mutation analysis revealed patients with bullae. Renal disease was reported to be absent
no C282Y or H63D mutation. The patient’s HLA type was in 17 cases; the presence or absence of renal disease was not
A*02, B*07, B*15. The patient recovered slowly after admin- indicated for 10 cases.
istration of doxycycline, ceftazidime, and levofloxacin therapy;
surgical debridement of the infected arm; and continuation of
hemodialysis. DISCUSSION
Infections with V. vulnificus are reported frequently in states
METHODS adjacent to the Gulf of Mexico in the United States and in
other geographic areas, many of which are also contiguous to
Laboratory methods. Blood cell counts, serum biochemis-
warm seas [15, 16]. In the southeastern United States, onset
try analyses, and coagulation studies were performed using
of illness with V. vulnificus infection usually occurs during
standard automated clinical methods. HLA-A and -B alleles
March through November, with the peak number of cases oc-
were detected using low-resolution DNA-based typing (PCR/
curring in May [17]. The median ages of patients who develop
sequence-specific oligonucleotide probe) [13]. Genotyping for
Vibrio septicemia or wound infections in this geographic area
the common HFE missense mutations C282Y (exon 4; nt
are 63 and 61 years, respectively [7]. These observations are
845GrA) and H63D (exon 2; nt 187CrG) was performed
consistent with the month of disease onset and ages of the
using genomic DNA obtained from peripheral blood speci-
present patient and of additional cases reported to the Alabama
mens [13]; evaluation for uncommon HFE alleles was not per-
Department of Public Health in the period of 1996–2002.
formed [14].
Most infections are attributable to ingestion of uncooked
Review of V. vulnificus infections reported in Alabama.
shellfish (typically raw oysters) or seawater contamination of
We requested information from the Alabama Department of
superficial wounds [1, 8, 15–18]. The history of ingestion of
Public Health (Montgomery) regarding reports of V. vulnificus
raw oysters by the present patient is consistent with the oc-
infection and pertinent patient data, including age at diagnosis,
currence of V. vulnificus in oysters harvested in Alabama coastal
sex, race, and reports of concurrent renal disease.
waters [19] and with other reports of persons with V. vulnificus
infections in this geographic area [15, 20, 21]. The development
RESULTS of bullae is typical of V. vulnificus bacteremia [7], although the
results of blood cultures in the present case were negative.
Data collected on Centers for Disease Control and Prevention Because V. vulnificus can survive for 24 h on skin [21], the
Cholera and Other Vibrio Illness Surveillance Report forms possibility that infection in the present patient was due to in-
(CDC 52.79; revised November 1998) by the Alabama De- oculation of areas of minor trauma by his handling of raw
partment of Public Health were returned for the years 1996– oysters or their shells cannot be excluded. It is also possible
2002. There were a total of 31 reports of V. vulnificus infection, that the presence of the arteriovenous dialysis fistula increased
including the case described here. The mean age (SD) of the likelihood that the present patient would develop bullae
these patients at diagnosis was 56 16 years (range, 24–86 due to Vibrio infection in the same extremity, although this is
years). Twenty-seven patients were men, and 4 were women. unproven.
e64 • CID 2003:37 (1 September) • Barton et al.Chronic liver disease, alcoholism, diabetes mellitus, immu- in patients undergoing long-term hemodialysis has been di-
nodeficiencies, hemochromatosis or other iron overload dis- rectly related to the dose of intravenous iron [32].
orders, inheritance of HFE mutations, and receipt of iron che- Anemia associated with iron deficiency is common among
lation therapy increase susceptibility to Vibrio infection [1–5, persons treated with long-term hemodialysis [33–35]. Serum
16]. It is unknown whether the present patient had cirrho- iron values in the present patient indicate that he was iron
sis or other chronic liver disease, because liver biopsy was replete and had hyperferritinemia, although we did not measure
not performed; however, there was otherwise no evidence of his plasma concentrations of free hemoglobin. In mice, how-
chronic liver disease. He did not have a hemochromatosis phe- ever, the lethality of intraperitoneal V. vulnificus was found to
notype [13], a common HFE mutation [13, 14], or an HLA be directly related to the plasma concentration of hemoglobin,
immunophenotype typical of hemochromatosis in Alabama and increased susceptibility to V. vulnificus infection lasted be-
[22]; diabetes mellitus; a history of unusual, frequent, or severe yond the time when hemoglobin levels had returned to normal
infections; or subnormal concentrations of total serum IgG or [36]. V. vulnificus also produces a cytotoxic hemolysin [24] that
IgG subclasses. We were unable to identify reports in which could make hemoglobin iron more readily available in the
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erythropoietin therapy was believed to increase susceptibility blood or in a wound.
to infection. Taken together, these observations suggest that In vitro studies of blood neutrophils in persons treated with
chronic renal insufficiency, chronic hemodialysis, or therapy chronic hemodialysis have demonstrated several functional ab-
with intravenous iron sucrose could account for the patient’s normalities that may decrease resistance to V. vulnificus infec-
susceptibility to V. vulnificus infection. This is consistent with tion. These include depressed phagocytosis [37, 38], impaired
reports of V. vulnificus infections in other persons in Alabama hydrogen peroxide production [37], and decreased chemilu-
who had renal disease. Furthermore, there are reports of 2 oth- minescence due to superoxide anion–independent mechanisms
er patients with chronic renal disease who had V. vulnificus [39]. Furthermore, serum from patients undergoing long-term
infection [4, 9]. One also had transfusion iron overload [9], hemodialysis has been found to be less effective than serum
and the other had hypogammaglobulinemia due to nephrotic from healthy subjects at opsonizing zymosan particles in a neu-
syndrome [4]. trophil phagocytosis assay system [38]. It is consistent with
V. vulnificus does not grow in human serum or tissue unless these reports that there was a significant negative correlation
iron is readily available [2, 16, 23, 24]. In the present patient, between the survival of V. vulnificus in the whole blood of
iron could have been available because of his low unbound persons treated with long-term hemodialysis and neutrophil
iron–binding capacity of transferrin, receipt of infusions of iron phagocytosis in vitro, and there was evidence that V. vulnificus
sucrose, and hyperferritinemia. The serum unbound iron– also resists phagocytosis by its possession of an antiphagocytic
binding capacity in patients who require hemodialysis is usually surface antigen [40].
lower than that in persons without renal failure [11, 12, 25, There are several approaches to reducing the risk of Vibrio
26]. Like the present patient, most persons treated with chronic infection in persons treated with long-term hemodialysis and
hemodialysis receive intravenous iron infusions and erythro- periodic intravenous iron infusions. It is prudent for nephrol-
poietin for treatment of anemia [11, 12, 27]. In such patients, ogists and other physicians to inform all such patients of the
serum non–transferrin-bound iron is often detected before iron risk of Vibrio infection associated with eating raw shellfish and
infusions, and the non–transferrin-bound iron level and trans- that they should avoid consumption of all uncooked shellfish
ferrin saturation are increased significantly after infusions [28, harvested in warm seas. Forty-eight percent of persons treated
29]. Greater survival of V. vulnificus in the whole blood of with long-term hemodialysis in the Washington, D.C., area
patients who undergo hemodialysis is associated with greater reported that they had eaten raw oysters after having kidney
serum transferrin iron saturation levels and greater serum fer- disease diagnosed [41]. Thus, education of patients undergoing
ritin concentrations [30]. Although these iron-related values long-term hemodialysis about V. vulnificus is likely to decrease
were not measured in the present patient when his infection their consumption of raw shellfish [41]. Advisories that persons
probably started, his serum transferrin saturation was main- with chronic renal disease should not eat uncooked shellfish may
tained at ⭓30% and his serum ferritin concentration at ⭓300 also be effective when displayed at all points of sale of uncooked
ng/mL by iron sucrose infusions. Abnormal iron metabolism oysters or other shellfish [1, 15]. Intravenous iron infusions are
in persons treated with chronic hemodialysis is also associated typically administered to patients who are being treated with
with loss of ability of their serum to resist growth of Staphy- long-term hemodialysis because they are relatively safe and ef-
lococcus epidermidis in vitro [28] and with increased in vivo fective [10–12, 27]. However, it seems prudent to maintain the
susceptibility to infection with Yersinia species [31]. In agree- lowest serum concentrations of iron, transferrin saturation, and
ment with these observations, the risk of infections of all types ferritin that are consistent with an acceptable blood hemoglobin
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